The compound 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (1), commonly known as Ibrutinib, is described in WO 2008/039218 A2, for instance, in Example 1b. Ibrutinib is marketed in the United States as IMBRUVICA®, and is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Crystalline forms of Ibrutinib are known, and have been disclosed, for example, in WO 2013/184572 A1, which reports non-solvated Ibrutinib Forms A, B and C, as well as solvated Forms D, E and F, formed with methyl isobutyl ketone, toluene and methanol, respectively. Further crystalline forms, including anhydrous, solvated and co-crystal forms are reported, for example, in WO 2015/081180 A1, WO 2015/145415 A2, CN 103923084 A, WO 2016/025720 A1, CN 105294696 A, CN 105646498 A, CN 105646499 A, CN105646484 A, WO 2016/079216 A1, WO 2016/139588 A1, CN 106008529 A, WO 2016/150349 A1, WO 2016/170545 A1, WO 2016/156127 A1, WO 2016/160598 A1 and WO 2016/160604 A1.
According to publicly available regulatory approval documents for Ibrutinib, such as the Australian Public Assessment Report (AusPAR), the drug substance Ibrutinib in the approved drug product IMBRUVICA®, is anhydrous Form A. This form of the drug substance is reported to exhibit pH dependent solubility, and to fall within Class II of the Biopharmaceutics Classification System (BCS). Class II drug substances have high permeability but low solubility, which can present a challenge to achieving good bioavailability. Other anhydrous forms of Ibrutinib, including Form B, are also reported to have low aqueous solubility. Known approaches to improving solubility and/or dissolution, and potentially the bioavailability, of a particular crystalline form of a Class II drug substance include, for example, particle size reduction techniques, formulation of the drug substance as the amorphous form, and formulation together with solubilizing excipients. According to the European CHMP Assessment Report (EMA/CHMP/645137/2014), the drug substance Ibrutinib in the approved drug product IMBRUVICA®, is subjected to micronization to facilitate dissolution in the drug product.
In some cases, the use of solvated forms of a drug substance can be useful in the development of a low solubility drug substance such as Ibrutinib since incorporation of a solvent molecule into the crystal lattice of a substance can directly alter the solubility and/or dissolution characteristics of the substance. Depending on the pharmaceutical acceptability and toxicity of the solvent, such a solvate form can be formulated to provide a drug product having enhanced dissolution and potentially improved bioavailability.
Additionally, solvated crystalline forms of Ibrutinib may be useful as intermediates in the provision of amorphous forms of Ibrutinib. Although amorphous forms of a drug substance typically exhibit more favourable solubility and/or dissolution characteristics than corresponding crystalline forms, achieving the high purity required for the bulk drug substance can be challenging when using amorphous forms owing to the nature of the processes typically employed for their preparation, such as spray drying, evaporation and lyophilisation. Unlike crystallization procedures, such preparative procedures do not allow for purification of the drug by separation of the drug from impurities that remain dissolved in the crystallization solvent. As a result, when employing these techniques for the preparation of amorphous forms, the purity of the input drug must equal or exceed the expected purity of the final bulk drug substance. When crystalline forms of a drug are not used as intermediates in the preparation of an amorphous drug substance, it is necessary to purify the drug by non-crystallographic techniques, which can complicate a commercial manufacturing process, or to conduct any necessary purification procedures on an earlier intermediate compound in the synthesis of the drug (with the further requirement that conversion of this intermediate to the drug does not result in the introduction of further impurities). In this way, crystalline solvate forms of Ibrutinib, which may be useful in the provision of amorphous forms of Ibrutinib, can contribute to the development of procedures for improving the dissolution properties of this drug substance.
Although solvates may be sought after, predicting the properties of an as yet undiscovered solvate form of a drug substance is currently not possible. Further, there is no way to predict whether a drug substance and solvent molecule will co-crystallize in the same crystal lattice, or the conditions under which co-crystallization will occur. Unlike the formation of salts, solvate formation is not aided by the formation of a strong ionic bond between acidic and basic moieties, but instead relies upon weaker non-ionic interactions.
Known solvated and hydrated crystalline forms of Ibrutinib are associated with various problems, such as reproducibility problems associated with the variable incorporation of water/solvent, low onset of dehydration of hydrated forms, the incorporation or use of toxic or questionable solvents for which no adequate safety data is available according to established ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines such as Q3C(R5), or preparations that are impractical for commercial use. The tendency of forms to dehydrate limits their usefulness in commercial products since it requires specialized practices to avoid dehydration during drying, handling, storage and formulation activities. Furthermore, the variable and/or undefined nature of some of these forms has regulatory implications, as the characteristics of an active pharmaceutical ingredient must be well-defined and controlled.
Different crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different crystalline forms may have different stability properties. A particular crystalline form may be more sensitive to heat, relative humidity (RH) and/or light. Alternatively or additionally, a particular crystalline form may provide more compressibility and/or density properties thereby providing more desirable characteristics for formulation and/or product manufacturing. Particular crystalline forms may also have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets. Differences in stability may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, such as a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Different physical properties of crystalline forms may also affect their processing. For example, a particular crystalline form may be more resistant to flow, or may be more difficult to filter and/or wash.
Although general approaches to crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. Furthermore, prediction of the properties of any unknown crystalline forms, and how they will differ from other crystalline forms of the same compound, remains even more elusive (Joel Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, New York, 2002, page 9).
Therefore, there exists a need for novel crystalline forms of Ibrutinib for use in providing improved drug products containing Ibrutinib and their manufacture.